Elsevier

Neuroscience

Volume 154, Issue 3, 26 June 2008, Pages 978-993
Neuroscience

Cellular neuroscience
Status epilepticus induces a TrkB to p75 neurotrophin receptor switch and increases brain-derived neurotrophic factor interaction with p75 neurotrophin receptor: An initial event in neuronal injury induction

https://doi.org/10.1016/j.neuroscience.2008.04.038Get rights and content

Abstract

In neuronal cultures it has been demonstrated that neurotrophins can elicit neuronal death through the p75 neurotrophic receptor (p75ntr) in the absence of concomitant Trk signaling. However, it was suggested that p75ntr induces neuronal death after status epilepticus (SE) in neuronal populations that express relatively high quantities of tropomyosin receptor kinase B (TrkB). Here, using Western blot and immunohistochemistry analyses in the hippocampus, we found that 3-h SE caused a remarkable decrease in TrkB expression and phosphorylation, and a significant increase in p75ntr. TrkB modification occurs before the overexpression of the tumor suppressor protein p53, accompanies the cell damage taking place in the dentate gyrus, and precedes the CA1 neuronal injury as assessed by Fluoro-Jade B and Nissl staining. Co-immunoprecipitation of brain-derived neurotrophic factor (BDNF) or its immature form proBDNF showed increased interaction with p75ntr after its binding to TrkB was reduced. Interestingly, proBDNF also increases its binding with p75ntr after seizures that do not cause neuronal death (animals injected with pilocarpine that fail to enter SE). However, in those animals, TrkB protein levels remained unchanged and its phosphorylation increased. Our results indicate an intrinsic capacity of neurons in vivo to modify final neurotrophin output by changing the proportion of their receptors' expression and the receptors' interaction with their ligands. These early events support the idea that neurotrophins may be involved in the induction of neuronal death in vivo under pathological conditions.

Section snippets

Animals and induction of SE

Adult male Wistar rats (Instituto Ferreyra, Córdoba, Argentina) aged 2–2.5 months and weighing 250–320 g were used and housed under environmentally controlled conditions. Animals received water and food ad libitum, and were maintained in a 12-h light/dark cycle. The experimental protocol for this study followed the guidelines of the USA National Research Council Guide for the Care and Use of Laboratory Animals (National Research Council, 1996) and was approved by the Animal Care and Use

SE decreases TrkB and increase p75ntr protein levels

In order to make inferences on the possible roles of BDNF in vivo after CNS injury, it is necessary to determine the possible modifications of the whole BDNF signaling system (TrkB, p75ntr, sortilin, mature BDNF and proBDNF). Systemic administration of pilocarpine leads to SE, characterized by intense seizures of a sustained nature, typically starting with violent, generalized clonic–tonic seizures. Animals were allowed to remain in this condition for 3 h, exhibiting continuous myoclonus of

Discussion

Since the discovery that neurotrophins (NT) can regulate not only neuronal survival and differentiation but also neuronal apoptosis (Barret and Bartlet 1994, Frade et al 1996, Frade et al 1997), many questions have arisen regarding how such opposite functions can be regulated by the same signaling protein. In the present study we show that SE induces a switch between TrkB and p75ntr receptor levels, forcing BDNF to interact largely with one receptor rather than the other, an event that might

Acknowledgments

This work was supported by grants from CONICET, FONCYT (PICT 5-14398) and SECyT-UNC. D.H.M. is a career member of CONICET; N.U. and A.A. are recipients of doctoral fellowships from CONICET. We thank Laura Montroull for her help with some experiments.

References (96)

  • C.M. Gall

    Seizures-induced changes in neurotrophin expression: implications for epilepsy

    Exp Neurol

    (1993)
  • E. Goutan et al.

    BDNF, and full length and trunkated TrkB expression in the hippocampus of rat following kainic acid excitotoxic damageEvidence of complex time-dependent and cell-specific responses

    Mol Brain Res

    (1998)
  • J.V. Heymach et al.

    The biosynthesis of neurotrophin heterodimers by transfected mammalian cells

    J Biol Chem

    (1995)
  • L. Hicke

    Gettin' down with ubiquitin: turning off cell-surface receptors, transporters and channels

    Trends Cell Biol

    (1999)
  • P.E. Hughes et al.

    Excitotoxic lesion of rat brain with quinolinic acid induces expression of p53 messenger RNA and protein and p53-inducible genes Bax and Gadd-45 in brain areas showing DNA fragmentation

    Neuroscience

    (1996)
  • D.R. Kaplan et al.

    Neurotrophin signal transduction in the nervous system

    Curr Opin Neurobiol

    (2000)
  • A. Kondratyev et al.

    Electroconvulsive shock exposure prevents neuronal apoptosis after kainic acid-evoked status epilepticus

    Mol Brain Res

    (2001)
  • V. Lessmann et al.

    Neurotrophin secretion: current facts and future prospects

    Prog Neurobiol

    (2003)
  • M.S. Linggi et al.

    Neurotrophin receptor interacting factor (NRIF) is an essential mediator of apoptotic signaling by the p75 neurotrophin receptor

    J Biol Chem

    (2005)
  • W. Liu et al.

    Status epilepticus induces p53 sequence-specific DNA binding in mature rat brain

    Mol Brain Res

    (1999)
  • B. Michalski et al.

    Pro-brain-derived neurotrophic factor is decreased in parietal cortex in Alzheimer's disease

    Mol Brain Res

    (2003)
  • S.J. Mowla et al.

    Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor

    J Biol Chem

    (2001)
  • A. Nykjaer et al.

    p75NTR: live or let die

    Curr Opin Neurobiol

    (2005)
  • J.L. Poirier et al.

    Differential progression of dark neuron and Fluoro-Jade labelling in the rat hippocampus following pilocarpine-induced status epilepticus

    Neuroscience

    (2000)
  • F.R. Poulsen et al.

    Differential expression of brain-derived neurotrophic factor transcripts after pilocarpine-induced seizure-like activity is related to mode of Ca2+ entry

    Neuroscience

    (2004)
  • R.J. Racine

    Modifications of seizure activity by electrical stimulationII. Motor seizure

    Electroencephalogr Clin Neurophysiol

    (1972)
  • J.S. Rudge et al.

    Endogenous BDNF protein is increased in adult rat hippocampus after a kainic acid induced excitotoxic insult but exogenous BDNF is not neuroprotective

    Exp Neurol

    (1998)
  • L.C. Schmued et al.

    Fluoro-Jade: a novel fluorochrome for the sensitive and reliable histochemical localization of neuronal degeneration

    Brain Res

    (1997)
  • S. Schnydrig et al.

    Peripheral lipopolysaccharide administration transiently affects expression of brain-derived neurotrophic factor, corticotropin and proopiomelanocortin in mouse brain

    Neurosci Lett

    (2007)
  • M. Silhol et al.

    Spatial memory training modifies the expression of brain-derived neurotrophic factor tyrosine kinase receptors in young and aged rats

    Neuroscience

    (2007)
  • M.T. Sommerfeld et al.

    Down-regulation of the neurotrophin receptor TrkB following ligand bindingEvidence for an involvement of the proteasome and differential regulation of TrkA and TrkB

    J Biol Chem

    (2000)
  • Z. Tan et al.

    Differential induction of p53 in immature and adult rat brain following lithium-pilocarpine status epilepticus

    Brain Res

    (2002)
  • Z. Tan et al.

    Immunohistochemical study of p53-associated proteins in rat brain following lithium-pilocarpine status epilepticus

    Brain Res

    (2002)
  • E. Tremblay et al.

    Maturation of kainic acid seizure-brain damage syndrome in the ratI. Clinical, electrographic and metabolic observations

    Neuroscience

    (1984)
  • C.M. Troy et al.

    Mechanisms of p75-mediated death of hippocampal neuronsRole of caspases

    J Biol Chem

    (2002)
  • G.R. Ullal et al.

    NT-3 modulates BDNF and proBDNF levels in naïve and kindled rat hippocampus

    Neurochem Int

    (2007)
  • C.J. Wen et al.

    hNRAGE, a human neurotrophin receptor interacting MAGE homologue, regulates p53 transcriptional activity and inhibits cell proliferation

    FEBS Lett

    (2004)
  • B. Xu et al.

    The effects of brain-derived neurotrophic factor (BDNF) administration on kindling induction, Trk expression and seizure-related morphological changes

    Neuroscience

    (2004)
  • M.C. Zaccaro et al.

    p75 Co-receptors regulate ligand-dependent and ligand-independent Trk receptor activation, in part by altering Trk docking subdomains

    J Biol Chem

    (2001)
  • R.S. Aloyz et al.

    P53 is essential for development neuronal death as regulated by the TrkA and p75ntr receptors

    J Cell Biol

    (1998)
  • S.X. Bamji et al.

    The p75ntr mediates neuronal apoptosis and is essential for naturally occurring sympathetic neuron death

    J Cell Biol

    (1998)
  • M. Barbacid

    The Trk family of neurotrophin receptors

    J Neurbiol

    (1994)
  • G.L. Barret et al.

    The p75 nerve growth factor receptor mediates survival or death depending on the stage of sensory neuron development

    Proc Natl Acad Sci U S A

    (1994)
  • J.L. Berkeley et al.

    The role of muscarinic acetylcholine receptor-mediated activation of ERK 1/2 in pilocarpine-induced seizures

    J Neurochem

    (2002)
  • G. Biagini et al.

    Brain-derived neurotrophic factor superinduction parallels anti-epileptic-neuroprotective treatment in the pilocarpine epilepsy model

    J Neurochem

    (2001)
  • M. Bibel et al.

    Neurotrophins: Key regulators of cell fate and cell shape in the vertebrate nervous system

    Genes Dev

    (2000)
  • M. Bibel et al.

    Biochemical and functional interactions between the neurotrophin receptors trk and p75NTR

    EMBO J

    (1999)
  • D.K. Binder et al.

    Immunohistochemical evidence of seizure-induced activation of trk receptors in the mossy fiber pathway of adult rat hippocampus

    J Neurosci

    (1999)
  • Cited by (48)

    • Beyond good and evil: A putative continuum-sorting hypothesis for the functional role of proBDNF/BDNF-propeptide/mBDNF in antidepressant treatment

      2018, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      Since antidepressants can modulate neuronal activity, they may also subjugate the balance of mBDNF/proBDNF and/or mBDNF/propeptide to promote more efficient neuronal networking, thus favoring neuroplasticity on demand. It is worth noting that detrimental stimuli, such as status epilepticus, can also change the balance of hippocampal TrkB/p75R signaling by switching TrkB towards p75R expression and then favoring either mBDNF or proBDNF receptor binding (Unsain et al., 2008). In this scenario, the antidepressants become a type of “organizer”, by allowing the (re) balance between TrkB and p75R signaling, by amplifying neuroplastic possibilities toward fine-tuning of neuronal networking on demand of contingencies and specific requirements.

    • Calpain-dependent truncated form of TrkB-FL increases in neurodegenerative processes

      2016, Molecular and Cellular Neuroscience
      Citation Excerpt :

      The cleavage products of calpains action on their substrate may show biological activity (Ma, 2013). One of the most distinctive features of SE is that it induces an increase in the levels of BDNF and proBDNF, as well as an imbalance in the expression of their receptors, TrkB and p75ntr, respectively, before the onset of neuronal death, a feature shared with other neurodegenerative diseases (Unsain et al., 2008, 2009; Brito et al., 2013). In this regard, it has been demonstrated in models of ischemia, Alzheimer disease (AD) and SE, that calpain can process TrkB full-length (TrkB-FL), producing a cleaved receptor, the truncated TrkB-FL (Tc TrkB-FL), which is similar to the splice-variant TrkB T1 in that both receptors lack most of the intracellular domain.

    View all citing articles on Scopus
    1

    Present address: Natural Sciences Department, Hostos Community College, City University of New York.

    View full text